以 PAK1 为靶点可有效对抗合成小鼠模型中的皮肤鳞状细胞癌。

IF 4.5 2区 医学 Q1 ONCOLOGY
Cancer Science Pub Date : 2024-06-19 DOI:10.1111/cas.16246
Kazuhiro Okumura, Takao Morinaga, Megumi Saito, Yurika Tokunaga, Keisuke Otoyama, Sora Tanaka, Eriko Isogai, Masahito Kawazu, Yosuke Togashi, Yoshinori Hasegawa, Yuichi Wakabayashi
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引用次数: 0

摘要

通过对小鼠进行正向遗传分析,我们证明了 Pak1 在 DMBA/TPA 皮肤癌的发生过程中起着至关重要的作用。尽管 Pak1 被认为会促进癌症的发生,但人们对其整体功能仍知之甚少。为了详细阐明 Pak1 的功能意义,我们试图评估针对 PAK1 的异位抑制剂(NVS-PAK1-1)对合成小鼠模型可能产生的影响。为此,我们建立了两个细胞系,9AS1 和 19AS1,这两个细胞系来源于 DMBA/TPA 诱导的鳞状细胞癌 (SCC),并移植到 FVB 小鼠体内。根据我们目前的研究结果,NVS-PAK1-1 能显著抑制 9AS1 和 19AS1 细胞在体外和体内的肿瘤生长。对移植肿瘤的 RNA 序列分析表明,NVS-PAK1-1 能明显促进表皮细胞分化,并增强移植肿瘤的免疫反应。与这些观察结果一致的是,通过免疫组化分析,我们发现经 NVS-PAK1-1 处理的肿瘤中泛角蛋白阳性区域扩大,CD8 阳性免疫细胞的浸润可能增加。总之,我们目前的研究结果有力地表明,PAK1 与 SCC 的发展密切相关,抑制 PAK1 是一种很有前景的 SCC 治疗策略。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Targeting PAK1 is effective against cutaneous squamous cell carcinoma in a syngenic mouse model

Targeting PAK1 is effective against cutaneous squamous cell carcinoma in a syngenic mouse model

Targeting PAK1 is effective against cutaneous squamous cell carcinoma in a syngenic mouse model

By taking advantage of forward genetic analysis in mice, we have demonstrated that Pak1 plays a crucial role during DMBA/TPA skin carcinogenesis. Although Pak1 has been considered to promote cancer development, its overall function remains poorly understood. To clarify the functional significance of Pak1 in detail, we sought to evaluate the possible effect of an allosteric inhibitor against PAK1 (NVS-PAK1-1) on a syngeneic mouse model. To this end, we established two cell lines, 9AS1 and 19AS1, derived from DMBA/TPA-induced squamous cell carcinoma (SCC) that engrafted in FVB mice. Based on our present results, NVS-PAK1-1 treatment significantly inhibited the growth of tumors derived from 9AS1 and 19AS1 cells in vitro and in vivo. RNA-sequencing analysis on the engrafted tumors indicates that NVS-PAK1-1 markedly potentiates the epidermal cell differentiation and enhances the immune response in the engrafted tumors. Consistent with these observations, we found an expansion of Pan-keratin-positive regions and potentially elevated infiltration of CD8-positive immune cells in NVS-PAK1-1-treated tumors as examined by immunohistochemical analyses. Together, our present findings strongly suggest that PAK1 is tightly linked to the development of SCC, and that its inhibition is a promising therapeutic strategy against SCC.

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来源期刊
Cancer Science
Cancer Science 医学-肿瘤学
自引率
3.50%
发文量
406
审稿时长
2 months
期刊介绍: Cancer Science (formerly Japanese Journal of Cancer Research) is a monthly publication of the Japanese Cancer Association. First published in 1907, the Journal continues to publish original articles, editorials, and letters to the editor, describing original research in the fields of basic, translational and clinical cancer research. The Journal also accepts reports and case reports. Cancer Science aims to present highly significant and timely findings that have a significant clinical impact on oncologists or that may alter the disease concept of a tumor. The Journal will not publish case reports that describe a rare tumor or condition without new findings to be added to previous reports; combination of different tumors without new suggestive findings for oncological research; remarkable effect of already known treatments without suggestive data to explain the exceptional result. Review articles may also be published.
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